There are large individual differences among humans and animals in behavioral, physiological and toxicological responses to drugs of abuse. Many of these individual differences in behavioral responses to drugs display substantial genetic components. Transgenic animals provide means for approaching three interrelated goals: 1) Identification of gene elements that confer cell-type specific expression and may thus allow targeting of introduced genetic material to appropriate brain regions; 2) Elucidation of gene elements yielding trans-synaptic gene regulation and thus allowing appropriate regulated expression of introduced genetic material; and 3) Ascertainment of biochemical and behavioral consequences of the introduction of or disruption of specific genes. Dopaminergic systems involvement in central mechanisms of reward and reinforcement, and involvement of pre- and post-synaptic opioid peptide systems in the effects of opiate drugs has led to continuing focus on these systems during this year. Failure to reduce cocaine reward in DAT knockout mice, reported during last year, has also led to expansion of efforts to studies of SERT and NET knockout mice. Each of these assessments has provided novel data concerning the relationship between expression of each of these gene products at normal levels and drug-induced behavioral changes. In particular, studies of mice without combinations of DAT, VMAT2, SERT, NET or dopamine and serotonin receptor subtypes in providing striking evidence for mechanisms of cocaine and amphetamine reward and sleep/wake regulation. - knockout mice cocaine amphetamine morphine heroin